The overall goal of this project is to enable mechanistic understanding and quantitative prediction of the influence of ingested lipids and food on orally delivered compound absorption. Lipids and food can enhance oral absorption of some compounds several hundred percent; however, they can also cause several-fold decreases in absorption, or have no effect. These effects are not currently amenable to quantitative prediction, yet hold tremendous significance with respect to drug delivery, nutrition, and food-related diseases. While previous studies have probed specific aspects of lipid and food function in the gastrointestinal (GI) tract, it is proposed that an integrated, systems based approach considering multiple parallel, dynamic processes (compound dissolution, lipid digestion, partitioning into colloidal phases, absorption) will enable quantitative understanding and prediction. An experimental and theoretical framework has been developed by the PI’s lab and used successfully to predict the impact of lipids (long chain triglycerides) on drug absorption and pharmacokinetics (PK). In this project, we will build from these initial efforts to enable understanding and prediction of the impact of complex food composition and structure. In the first aim, the impact of complex food structure and composition on kinetics of digestion and co-delivered compound dissolution/partitioning into colloids will be studied. While it is recognized that food composition and structure are highly variable and complex, the proposed approach is to systematically test the impact of increasing complexity on physical and chemical properties of a controlled dynamic biorelevant in vitro system, coupled with analysis of the inherently variable in vivo digestion system. Compounds studied will represent broad ranges of relevant physicochemical properties. In the second aim, the impact of lipids and food on mucosal transport processes will be explored in detail. Specifically, the stability of mixed bile micelles containing lipid digestion products in the intestinal mucus barrier will be studied using electron paramagnetic resonance (EPR), and the potential impact of lipid transcellular transport on co-delivered compound transport, including tendency for lymphatic transport, will be studied. A novel primary human intestinal tube model will be employed to enable visualization of the mucosal interface in these studies. Finally, in the third aim, the ability of the model to predict PK in vivo, including human food effect data, will be validated. The research team embodies the multidisciplinary expertise necessary to transform fundamental knowledge of lipid digestion to quantitative prediction: a chemical engineer with experimental and modeling expertise in lipid-based oral drug delivery, mucosal transport, and engineered intestinal systems; a chemist with expertise in EPR analysis of complex microenvironments, a bioengineer with advanced biomaterial and organ-on-chip expertise, and industrial partners representing leaders in studying and modeling food effects on oral drug delivery.